Brain Networks, Neurotransmitters and Psychedelics: Towards a Neurochemistry of Self-Awareness.

PURPOSE OF REVIEW: Self-awareness can be defined as the capacity of becoming the object of one's own awareness and, increasingly, it has been the target of scientific inquiry. Self-awareness has important clinical implications, and a better understanding of the neurochemical basis of self-awareness may help clarifying causes and developing interventions for different psychopathological conditions. The current article explores the relationship between neurochemistry and self-awareness, with special attention to the effects of psychedelics. RECENT FINDINGS: The functioning of self-related networks, such as the default-mode network and the salience network, and how these are influenced by different neurotransmitters is discussed. The impact of psychedelics on self-awareness is reviewed in relation to specific processes, such as interoception, body ownership, agency, metacognition, emotional regulation and autobiographical memory, within a framework based on predictive coding. Improved outcomes in emotional regulation and autobiographical memory have been observed in association with the use of psychedelics, suggesting higher-order self-awareness changes, which can be modulated by relaxation of priors and improved coping mechanisms linked to cognitive flexibility. Alterations in bodily self-awareness are less consistent, being potentially impacted by doses employed, differences in acute/long-term effects and the presence of clinical conditions. Future studies investigating the effects of different molecules in rebalancing connectivity between resting-state networks may lead to novel therapeutic approaches and the refinement of existing treatments.

Validation of the Psychological Insight Scale: A new scale to assess psychological insight following a psychedelic experience.

INTRODUCTION: As their name suggests, 'psychedelic' (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). METHODS: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific 'global psychedelic survey' study. RESULTS: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach's α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. CONCLUSION: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight - as measured by the PIS - was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Twenty percent better with 20 micrograms? A qualitative study of psychedelic microdosing self-rapports and discussions on YouTube.

BACKGROUND: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. METHODS: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. RESULTS: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. CONCLUSIONS: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

A New Index of Coordinated Posterior and Anterior Evoked EEG to Detect Recall Under Sedation - A Pilot Study.

EEG-based technologies may be limited in identifying recall under sedation (RUS). We developed a novel index, posteriorization/anteriorization (P/A) index, based on auditory evoked EEG signal and assessed whether it could differentiate between patients with or without RUS. Methods: EEG and BIS were sampled from 3 groups: 1. Patients undergoing sedation (n = 26); 2. Awake volunteers (n = 13, positive control for recall) 3. Patients undergoing general anesthesia (GA, n = 12, negative control for recall). In recovery, recall was assessed using the BRICE questionnaire. Of the 26 sedated patients, 12 experienced recall. Both The P/A index and BIS differentiated between patients with recall and no recall. However, BIS differentiation may have been sensitive to the main drug used for sedation (midazolam vs. propofol) and the P/A index did not show similar drug-based sensitivity. Furthermore, only BIS results were correlated with EMG. Conclusion: This pilot study provided support for the association between P/A index and recall after sedation. Further research is needed in integrating the index into clinical use: (1) it should be derived by an easy-to-use EEG system with a better signal-to-noise ratio; (2) its applicability to other drugs must be shown.

GABAergic Inhibition Gates Perceptual Awareness During Binocular Rivalry.

Binocular rivalry is a classic experimental tool to probe the neural machinery of perceptual awareness. During rivalry, perception alternates between the two eyes, and the ebb and flow of perception is modeled to rely on the strength of inhibitory interactions between competitive neuronal populations in visual cortex. As a result, rivalry has been suggested as a noninvasive perceptual marker of inhibitory signaling in visual cortex, and its putative disturbance in psychiatric conditions, including autism. Yet, direct evidence causally implicating inhibitory signaling in the dynamics of binocular rivalry is currently lacking. We previously found that people with higher GABA levels in visual cortex, measured using magnetic resonance spectroscopy, have stronger perceptual suppression during rivalry. Here, we present direct causal tests of the impact of GABAergic inhibition on rivalry dynamics, and the contribution of specific GABA receptors to these dynamics. In a crossover pharmacological design with male and female adult participants, we found that drugs that modulate the two dominant GABA receptor types in the brain, GABAA (clobazam) and GABAB (arbaclofen), increase perceptual suppression during rivalry relative to a placebo. Crucially, these results could not be explained by changes in reaction times or response criteria, as determined through rivalry simulation trials, suggesting a direct and specific influence of GABA on perceptual suppression. A full replication study of the GABAB modulator reinforces these findings. These results provide causal evidence for a link between the strength of inhibition in the brain and perceptual suppression during rivalry and have implications for psychiatric conditions including autism.SIGNIFICANCE STATEMENT How does the brain accomplish perceptual gating? Here we use a direct and causal pharmacological manipulation to present insight into the neural machinery of a classic illusion of perceptual awareness: binocular rivalry. We show that drugs that increase GABAergic inhibition in the brain, clobazam (GABAA modulator) and arbaclofen (GABAB modulator), increase perceptual suppression during rivalry relative to a placebo. These results present the first causal link between GABAergic inhibition and binocular rivalry in humans, complementing classic models of binocular rivalry, and have implications for our understanding of psychiatric conditions, such as autism, where binocular rivalry is posited as a behavioral marker of disruptions in inhibitory signaling in the brain.

Genetic Analysis of Patients Who Experienced Awareness with Recall while under General Anesthesia.

BACKGROUND: Intraoperative awareness with recall while under apparently adequate general anesthesia is a rare, unexplained, and often very distressing phenomenon. It is possible that a relatively small number of genetic variants might underlie the failure of general anesthetic drugs to adequately suppress explicit memory formation and recall in the presence of apparently adequate anesthesia concentrations. METHODS: The authors recruited 12 adult patients who had experienced an episode of intraoperative awareness with recall (compared with 12 controls), performed whole exome sequencing, and applied filtering to obtain a set of genetic variants that might be associated with intraoperative awareness with recall. The criteria were that the variant (1) had a minor allele frequency less than 0.1% in population databases, (2) was within exonic or splicing regions, (3) caused a nonsynonymous change, (4) was predicted to be functionally damaging, (5) was expressed in the top 50% of genes expressed in the brain, and (6) was within genes in Kyoto Encyclopedia of Genes and Genomes pathways associated with general anesthesia, drug metabolism, arousal, and memory. RESULTS: The authors identified 29 rare genetic variants in 27 genes that were absent in controls and could plausibly be associated with this disorder. One variant in CACNA1A was identified in two patients and two different variants were identified in both CACNA1A and CACNA1S. Of interest was the relative overrepresentation of variants in genes encoding calcium channels and purinergic receptors. CONCLUSIONS: Within the constraints of the filtering process used, the authors did not find any single gene variant or gene that was strongly associated with intraoperative awareness with recall. The authors report 27 candidate genes and associated pathways identified in this pilot project as targets of interest for future larger biologic and epidemiologic studies.

Interoceptive awareness is associated with acute alcohol-induced changes in subjective effects.

Interoception, the sensing of bodily signals, is related to emotional reactivity and may contribute to the pathophysiology of addiction. Evidence is accumulating that individuals with alcohol use disorders and other substance-dependences show altered interoceptive processing, however little is known about the acute effects of alcohol on interoception and how this may influence the perception of drug induced effects. In a double-blind design, fifty (30 females) healthy young participants were given a beverage containing either a low (0.4 g/kg, n = 18) or high (0.6 g/kg, n = 15) alcohol dose or a placebo (n = 17). After alcohol administration, participants completed two interoceptive paradigms, the heart-beat tracking and heart-beat discrimination tasks, both assessing different accuracy and metacognitive measures of interoception. Subjective feelings elicited by alcohol administration were also measured. Participants under the low alcohol dose had lower metacognitive interoceptive awareness on the discrimination task compared to placebo. Participants under alcohol experienced feelings of light-headedness, which were positively associated with increased interoceptive awareness in the cardiac discrimination task. These results provide evidence for a relationship between interoceptive processing and the perception of drug-induced mood changes. This finding, showing how interoceptive awareness of cardiac discrimination contributes to the appraisal of subjective light-headedness generated by alcohol administration, brings novel perspectives to the understanding of drug discrimination and reinforcement mechanisms.

Single-trial classification of awareness state during anesthesia by measuring critical dynamics of global brain activity.

In daily life, in the operating room and in the laboratory, the operational way to assess wakefulness and consciousness is through responsiveness. A number of studies suggest that the awake, conscious state is not the default behavior of an assembly of neurons, but rather a very special state of activity that has to be actively maintained and curated to support its functional properties. Thus responsiveness is a feature that requires active maintenance, such as a homeostatic mechanism to balance excitation and inhibition. In this work we developed a method for monitoring such maintenance processes, focusing on a specific signature of their behavior derived from the theory of dynamical systems: stability analysis of dynamical modes. When such mechanisms are at work, their modes of activity are at marginal stability, neither damped (stable) nor exponentially growing (unstable) but rather hovering in between. We have previously shown that, conversely, under induction of anesthesia those modes become more stable and thus less responsive, then reversed upon emergence to wakefulness. We take advantage of this effect to build a single-trial classifier which detects whether a subject is awake or unconscious achieving high performance. We show that our approach can be developed into a means for intra-operative monitoring of the depth of anesthesia, an application of fundamental importance to modern clinical practice.

The effects of illness severity, cognition, and estimated antipsychotic dopamine receptor occupancy on insight into the illness in schizophrenia: An analysis of clinical antipsychotic trials of intervention effectiveness (CATIE) data.

BACKGROUND: The relationship between dopamine D2 receptor (D2R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses. AIM AND METHODS: We investigated the influence of estimated D2R (Est.D2R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18-62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D2R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D2R. RESULTS: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D2R did not predict IIA, and Est.D2R did not serve either a moderating or mediating role in both regression and path analyses. CONCLUSIONS: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D2R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity.

An analysis of the effects of using Zolpidem and an innovative multimodal interdisciplinary team approach in prolonged disorders of consciousness (PDOC).

Zolpidem has been used with mixed effects in patients presenting with Prolonged Disorders of Consciousness (PDOC). This single case report describes an interdisciplinary team (IDT) protocol combined with Zolpidem 10 mg in a single case of a patient in PDOC. 'Emily', a 44-year-old lady was admitted to a rehabilitation unit in Ireland one year post onset of subarachnoid haemorrhage. Standardized assessments diagnosed her as being in a minimally conscious state (MCS). An IDT protocol was devised to stimulate and record responses to sensory and pharmacological stimuli. The protocol was applied pre and post administration of Zolpidem 10 mg. Across standardized measures of awareness, improved results post-Zolpidem were recorded. Spontaneous, appropriate verbalization was the most significant change observed 30 min after administration of Zolpidem 10 mg. This ceased after approximately 2 h with Emily reverting to a non-verbal state. The combined effect of Zolpidem and the IDT protocol applied over an eight-week period resulted in durable functional and communicative gains for Emily, inferring neuro-plasticity. This report highlights the impact of a combined approach of intensive IDT intervention in conjunction with Zolpidem. The use of Zolpidem with this patient population warrants further investigation.

Auditory Predictive Coding across Awareness States under Anesthesia: An Intracranial Electrophysiology Study.

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70-150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC.SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

Pre-sleep treatment with galantamine stimulates lucid dreaming: A double-blind, placebo-controlled, crossover study.

Lucid dreaming is a remarkable state of consciousness in which one is aware of the fact that one is dreaming while continuing to dream. Based on the strong relationship between physiological activation during rapid eye-movement sleep and lucid dreaming, our pilot research investigated whether enhancing cortical activation via acetylcholinesterease inhibition (AChEI) would increase the frequency of lucid dreams and found AChEI to be a promising method for lucid dream induction. In the current study we sought to quantify the size and reliability of the effect of AChEI on lucid dreaming, dream recall and dream content as well as to test the effectiveness of an integrated lucid dream induction protocol which combined cholinergic stimulation with other methods for lucid dream induction. Participants (N = 121) with high dream recall and an interest in lucid dreaming were randomly assigned counterbalanced orders of 3 doses of galantamine (0, 4 and 8 mg). On 3 consecutive nights, they awoke approximately 4.5 hours after lights out, recalled a dream, ingested the capsules and stayed out of bed for at least 30 minutes. Participants then returned to bed and practiced the Mnemonic Induction of Lucid Dreams technique while returning to sleep. The percentage of participants who reported a lucid dream was significantly increased for both 4 mg (27%, odds ratio = 2.29) and 8 mg doses (42%, odds ratio = 4.46) compared to the active placebo procedure (14%). Galantamine also significantly increased dream recall, sensory vividness and complexity (p<0.05). Dream recall, cognitive clarity, control, positive emotion, vividness and self-reflection were increased during lucid compared to non-lucid dreams (p<0.0001). These results show that galantamine increases the frequency of lucid dreams in a dose-related manner. Furthermore, the integrated method of taking galantamine in the last third of the night with at least 30 minutes of sleep interruption and with an appropriately focused mental set is one of the most effective methods for inducing lucid dreams available today.

Exploring the effects of galantamine paired with meditation and dream reliving on recalled dreams: Toward an integrated protocol for lucid dream induction and nightmare resolution.

An experimental home study examined the impact of a pre-sleep protocol for enhancing self-awareness, lucidity, and responsiveness in dreams. It included ingesting the cholinesterase inhibitor galantamine--which is widely reported to increase the frequency of lucid dreaming--prior to engaging in middle-of-the-night meditation and the imaginary reliving of a distressing dream while exercising new responses. Thirty-five participants completed an eight-night study, which included pre- and post-baseline nights and six conditions: waking for 40 min before returning to bed, called Wake-Back-to-Bed (WBTB); Wake-Back-to-Bed plus placebo (WBTB + P); Wake-Back-to-Bed plus galantamine (WBTB + G); meditation and dream reliving (MDR); meditation and dream reliving plus placebo (MDR + P); and meditation and dream reliving plus galantamine (MDR + G). The outcome measures included lucidity, reflectiveness, interactive behavior, role change, constructive action, and fear and threat, as measured by the participants' self-ratings. The results support the use of this protocol in further studies of lucid dream induction and nightmare/trauma resolution.

The effects of alcohol on heartbeat perception: Implications for anxiety.

INTRODUCTION: It is well established that some individuals self-medicate their anxiety with alcohol. Though much evidence exists that alcohol consumption can be negatively reinforcing, there remains uncertainty regarding what mediates the relationship between alcohol and anxiety. An unexplored possibility is that, for some, alcohol impairs interoceptive sensitivity (the ability to accurately perceive one's physiological state), thereby decreasing state anxiety. Consistent with this, highly accurate heartbeat perception is a risk factor both for elevated trait anxiety and anxiety disorders. However, the direct impact of alcohol on cardioceptive accuracy has not to our knowledge been previously examined. METHODS: Sixty-one social drinkers came to the lab in groups of 4-6 on two days spaced a week apart. Each participant was randomly assigned to receive alcoholic drinks targeting a BAC of 0.05% on one testing day and placebo drinks on the other, with the order counter-balanced. On both testing days, participants engaged in a Schandry heartbeat perception task on three occasions: at baseline, after an alcohol absorption period, and after physiological arousal was raised via exercise. RESULTS: For men only, alcohol significantly impaired cardioceptive accuracy relative to a placebo at both low and high levels of arousal, with medium to large effect sizes. CONCLUSIONS: Though preliminary, this finding is consistent with the proposed hypothesis linking alcohol consumption and anxiety, at least for men. Future studies should directly examine whether, among individuals with anxiety disorders, cardioceptive sensitivity mediates the relationship between alcohol consumption and state anxiety.

Gamma-Hydroxybutyrate Increases Resting-State Limbic Perfusion and Body and Emotion Awareness in Humans.

Gamma-hydroxybutyrate (GHB) is a GHB-/GABA-B receptor agonist inducing a broad spectrum of subjective effects including euphoria, disinhibition, and enhanced vitality. It is used as treatment for neuropsychiatric disorders including narcolepsy and alcohol withdrawal, but is also a drug of abuse. Non-medical users report enhancement of body and emotion awareness during intoxication. However, the neuronal underpinnings of such awareness alterations under GHB are unknown so far. The assessment of regional cerebral blood flow (rCBF) by pharmacological magnetic resonance imaging (phMRI) enables the elucidation of drug-induced functional brain alterations. Thus, we assessed the effects of GHB (35 mg/kg p.o.) in 17 healthy males on rCBF and subjective drug effects, using a placebo-controlled, double-blind, randomized, cross-over design employing arterial spin labeling phMRI. Compared to placebo, GHB increased subjective ratings for body and emotion awareness, and for dizziness (p<0.01-0.001, Bonferroni-corrected). A whole-brain analysis showed increased rCBF in the bilateral anterior cingulate cortex (ACC) and the right anterior insula under GHB (p<0.05, cluster-corrected). ACC and insula rCBF are correlated with relaxation, and body and emotion awareness (p<0.05-0.001, uncorrected). Interaction analyses revealed that GHB-induced increase of body awareness was accompanied by increased rCBF in ACC, whereas relaxation under GHB was accompanied by elevated rCBF in right anterior insula (p<0.05, uncorrected). In conclusion, enhancement of emotion and body awareness, and increased perfusion of insula and ACC bears implications both for the properties of GHB as a drug of abuse as well as for its putative personalized potential for specific therapeutic indications in affective disorders.

Bispectral Index monitoring in cancer patients undergoing palliative sedation: a preliminary report.

INTRODUCTION: Continuous palliative sedation (PS) is currently titrated based on clinical observation; however, it is often unclear if patients are still aware of their suffering. The aim of this prospective study is to characterize the level of consciousness in patients undergoing PS using Bispectral Index (BIS) monitoring. PATIENTS AND METHODS: We enrolled consecutive patients with refractory symptoms requiring PS. We documented the level of sedation using Ramsay Sedation Scale (RSS) and BIS at 0, 2, 4, 6, 12, and 24 h during the first day of PS and examined their degree of association. Intravenous midazolam or propofol was titrated according to the sedation level. RESULTS: Twenty patients on PS were recruited and had BIS continuous monitoring. Delirium was the most frequent reason for PS (n = 15, 75%). The median time of sedation was 24.5 h (interquartile range 6-46). The average time to achieve the desired sedation level was 6 h, and dose titration was required in 80% of the cases. At baseline, 14 (70%) patients were considered to be awake according to RSS (i.e., 1-3) and 19 (95%) were awake according to BIS (i.e., >60%). This proportion decreased to 31 and 56% at 4 h, 27% and 53 at 6 h, and 22 and 33% at 24 h. RS and BIS had moderate correlation (rho = -0.58 to -0.65); however, a small proportion of patients were found to be awake by BIS (i.e., ≥60%) despite clinical observation (i.e., RSS 4-6) indicating otherwise. CONCLUSIONS: The BIS is a noninvasive, bedside, real-time continuous monitoring method that may facilitate the objective assessment of level of consciousness and dose titration in patients undergoing PS.

Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects.

Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 µg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.

Levodopa medication improves incidental sequence learning in Parkinson's disease.

Empirical evidence suggests that levodopa medication used to treat the motor symptoms of Parkinson's disease (PD) may either improve, impair or not affect specific cognitive processes. This evidence led to the 'dopamine overdose' hypothesis that levodopa medication impairs performance on cognitive tasks if they recruit fronto-striatal circuits which are not yet dopamine-depleted in early PD and as a result the medication leads to an excess of dopamine. This hypothesis has been supported for various learning tasks including conditional associative learning, reversal learning, classification learning and intentional deterministic sequence learning, on all of which PD patients demonstrated significantly worse performance when tested on relative to off dopamine medication. Incidental sequence learning is impaired in PD, but how such learning is affected by dopaminergic therapy remains undetermined. The aim of the current study was to investigate the effect of dopaminergic medication on incidental sequence learning in PD. We used a probabilistic serial reaction time task (SRTT), a sequence learning paradigm considered to make the sequence less apparent and more likely to be learned incidentally rather than intentionally. We compared learning by the same group of PD patients (n=15) on two separate occasions following oral administration of levodopa medication (on state) and after overnight withdrawal of medication (off state). Our results demonstrate for the first time that levodopa medication enhances incidental learning of a probabilistic sequence on the serial reaction time task in PD. However, neither group significantly differed from performance of a control group without a neurological disease, which indicates the importance of within group comparisons for identifying deficits. Levodopa medication enhanced incidental learning by patients with PD on a probabilistic sequence learning paradigm even though the patients were not aware of the existence of the sequence or their acquired knowledge. The results suggest a role in acquiring incidental motor sequence learning for dorsal striatal areas strongly affected by dopamine depletion in early PD.

2B-Alert Web: An Open-Access Tool for Predicting the Effects of Sleep/Wake Schedules and Caffeine Consumption on Neurobehavioral Performance.

STUDY OBJECTIVES: Computational tools that predict the effects of daily sleep/wake amounts on neurobehavioral performance are critical components of fatigue management systems, allowing for the identification of periods during which individuals are at increased risk for performance errors. However, none of the existing computational tools is publicly available, and the commercially available tools do not account for the beneficial effects of caffeine on performance, limiting their practical utility. Here, we introduce 2B-Alert Web, an open-access tool for predicting neurobehavioral performance, which accounts for the effects of sleep/wake schedules, time of day, and caffeine consumption, while incorporating the latest scientific findings in sleep restriction, sleep extension, and recovery sleep. METHODS: We combined our validated Unified Model of Performance and our validated caffeine model to form a single, integrated modeling framework instantiated as a Web-enabled tool. 2B-Alert Web allows users to input daily sleep/wake schedules and caffeine consumption (dosage and time) to obtain group-average predictions of neurobehavioral performance based on psychomotor vigilance tasks. 2B-Alert Web is accessible at: https://2b-alert-web.bhsai.org. RESULTS: The 2B-Alert Web tool allows users to obtain predictions for mean response time, mean reciprocal response time, and number of lapses. The graphing tool allows for simultaneous display of up to seven different sleep/wake and caffeine schedules. The schedules and corresponding predicted outputs can be saved as a Microsoft Excel file; the corresponding plots can be saved as an image file. The schedules and predictions are erased when the user logs off, thereby maintaining privacy and confidentiality. CONCLUSIONS: The publicly accessible 2B-Alert Web tool is available for operators, schedulers, and neurobehavioral scientists as well as the general public to determine the impact of any given sleep/wake schedule, caffeine consumption, and time of day on performance of a group of individuals. This evidence-based tool can be used as a decision aid to design effective work schedules, guide the design of future sleep restriction and caffeine studies, and increase public awareness of the effects of sleep amounts, time of day, and caffeine on alertness.